Abstract: This proposal suggests a consilience of bold new concepts in genetics, stem cell biology, and functional magnetic resonance imaging (fMRI) to address a singular question that could never be tapped previously: can we directly map the functionality of stem cell-driven neural circuit regeneration in vivo? Despite the debilitating character of central nervous system (CNS) diseases, and the urgency for therapeutic development, the complex nature of the neural fabric underlying CNS diseases such as spinal cord injuries, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and stroke, substantially negate their viable cure to date. Here, the fundamental ability of stem cells to regenerate non-dividing cells, as well as recent development of induced pluripotent stem cells (IPSC) gives fresh impetus for a whole new class of innovative treatments where damaged neural circuitry might be partially or fully restored by stem-cell induced neurogenesis. We seek to be instrumental in this pivotal endeavor by introducing a completely novel way of directly assessing the functionality of stem cell driven neural circuitry in vivo. This will be achieved by combining genetic techniques that will introduce modulatory and/or reporting capability to neural cells based on its cell type. We will strategically introduce viral vectors to both the underlying neural circuit as well as transplanted stem cells. For stem cell transfection, we expect our proposed technique to allow modulatory/reporting capability from only those developing into specific cell types. This cell-specific modulation/reporting capability will then combined with a novel distortion-free fMRI imaging technique, permitting non-invasive and high-resolution visualization of the regeneration processes. This project, upon its success, will provide direct functional assessment capabilities for the regenerated nerve tissue in vivo. This in turn will provide key guidance for developing novel stem cell therapies for CNS diseases. Public Health Relevance: The complexity and functional nature of neural circuitry makes central nervous systems (CNS) diseases such as spinal cord injuries, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and stroke particularly challenging for therapeutic approaches. While recent development of induced pluripotent stem cells (IPSC) gives fresh impetus for a whole new class of innovative treatment landscapes for patients with debilitating CNS diseases, the ultimate functionality of stem cell induced CNS regeneration remains elusive. This project, upon its success, will provide direct and functional assessment capabilities for the regenerated nerve tissue in vivo. This in turn will provide key guidance for developing novel stem cell therapies for CNS diseases.